Compound discovered that boosts effect of vaccines against HIV and flu

Oxford University scientists have discovered a compound that greatly boosts the effect of vaccines against viruses like flu, HIV and herpes in mice.

An 'adjuvant' is a substance added to a vaccine to enhance the immune response and offer better protection against infection.

The Oxford University team, along with Swedish and US colleagues, have shown that a type of polymer called polyethyleneimine (PEI) is a potent adjuvant for test vaccines against HIV, flu and herpes when given in mice.

The researchers were part-funded by the UK Medical Research Council and report their findings in the journal Nature Biotechnology.

Mice given a single dose of a flu vaccine including PEI via a nasal droplet were completely protected against a lethal dose of flu. This was a marked improvement over mice given the flu vaccine without an adjuvant or in formulations with other adjuvants.

The Oxford researchers now intend to test the PEI adjuvant in ferrets, a better animal model for studying flu. They also want to understand how long the protection lasts for. It is likely to be a couple of years before a flu vaccine using the adjuvant could be tested in clinical trials in humans, the researchers say.

'Gaining complete protection against flu from just one immunisation is pretty unheard of, even in a study in mice,' says Professor Quentin Sattentau of the Dunn School of Pathology at Oxford University, who led the work. 'This gives us confidence that PEI has the potential to be a potent adjuvant for vaccines against viruses like flu or HIV, though there are many steps ahead if it is ever to be used in humans.'

HIV, flu and herpes are some of the most difficult targets to develop vaccines against. HIV and flu viruses are able to change and evolve to escape immune responses stimulated by vaccines. There aren't any effective vaccines against HIV and herpes as yet, and the flu vaccine needs reformulating each year and doesn't offer complete protection to everyone who receives it. Finding better adjuvants could help in developing more effective vaccines against these diseases.

Most vaccines include an adjuvant. The main ingredient of the vaccine – whether it is a dead or disabled pathogen, or just a part of the virus or bacteria causing the disease – primes the body's immune system so it knows what to attack in case of infection. But the adjuvant is needed as well to stimulate this process.

While the need for adjuvants in vaccines has been recognised for nearly 100 years, the way adjuvants work has only recently been understood. The result has been that only a small set of adjuvants is used in current vaccines, often for historical reasons.

The most common adjuvant by far is alum, an aluminium-containing compound that has been given in many different vaccines worldwide for decades. However, alum is not the most potent adjuvant for many vaccine designs.

'There is a need to develop new adjuvants to get the most appropriate immune response from vaccines,' says Professor Sattentau, who is also a James Martin Senior Fellow at the Oxford Martin School, University of Oxford.

The Oxford University team found that PEI, a standard polymer often used in genetic and cell biology, has strong adjuvant activity.

When included in a vaccine with a protein from HIV, flu or herpes virus, mice subsequently mounted a strong immune response against that virus. The immune response was stronger than with other adjuvants that are currently being investigated.

The team also showed that PEI is a potent adjuvant in rabbits, showing the effect is not just specific to mice and could be general.

Another potential advantage of PEI is that it works well as an adjuvant for 'mucosal vaccines'. These vaccines are taken up the nose or in the mouth and absorbed through the mucus-lined tissues there, getting rid of any pain and anxiety from a needle. Mucosal vaccines may also be better in some ways as mucosal tissues are the sites of infection for these diseases (airways for respiratory diseases, genital mucosa for HIV and herpes).

Professor Sattentau suggests that: 'In the best of all possible worlds, you could imagine people would have one dose of flu vaccine that they'd just sniff up their nose or put under their tongue. And that would be it: no injections and they'd be protected from flu for a number of years.

'It's just a vision for the future at the moment, but this promising adjuvant suggests it is a vision that is at least possible.'

* The body's immune system is made up of two arms: the innate immune system and the adaptive immune system. The adaptive immune system consists of the antibodies and immune cells (T and B cells) the body develops specifically to combat a particular foreign agent.

The innate immune system had been thought of as playing a more primitive, non-specific role in protecting against invaders like viruses and parasites. However, it is now realised that the innate immune system is essential in kicking off any immune response. It needs to be activated first to generate an adaptive immune response.

But the innate immune system doesn't just press the start button. It tailors the body's adaptive immune response, deciding on what particular mix of antibodies and T cells is needed and teaching them what to attack.

It is the adjuvants in vaccines that stimulate the innate immune system. So having the right adjuvant can help the body produce the most appropriate immune response to protect against future infection.

* The paper 'Polyethyleneimine is a potent mucosal adjuvant for glycoproteins with innate and adaptive immune activating properties' is to be published in the journal Nature Biotechnology with an embargo of 18:00 UK time / 13:00 US Eastern time on Sunday 26 August 2012.

* The study was funded by the UK Medical Research Council, European Commission, the International AIDS Vaccine Initiative (IAVI), the Bill and Melinda Gates Foundation and Dormeur Investment Service Ltd.

* Professor Sattentau is an investigator in the Jenner Institute at Oxford University and a James Martin Senior Fellow at the Oxford Martin School, Oxford University.

* For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

* The Oxford Martin School is a unique interdisciplinary community within the University of Oxford. The School fosters innovative thinking, deep scholarship and collaborative activity to address the most pressing risks and realise new opportunities of the 21st century. It was founded in 2005 through the vision and generosity of James Martin, and currently comprises over 35 interdisciplinary research programmes on global future challenges. The Oxford Martin School's Director is Ian Goldin, Professor at the University of Oxford. http://www.oxfordmartin.ox.ac.uk

* Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school.

From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.